1. Field of the Invention
Generally, the present invention relates to therapeutic nanodevices based on dendritic polymers. More specifically, the present invention relates to nanodevices for use in treating neuroinflammation and infections in maternal-fetal medicine.
2. Description of Related Art
Currently, there is a need to develop techniques and compounds that are able to effectively deliver bioactive agents to cells. While there are numerous systems under review for effectuating the delivery, the problems surrounding the delivery mechanisms have outweighed the usefulness of the systems. Examples of such systems include viral transfection systems and non-viral transfection systems. Viral systems typically have higher transfection efficiency than non-viral systems, but there have been questions regarding the safety of viral systems. In addition, viral vector preparation tends to be a complicated and expensive process. Although non-viral transfection systems generally are less efficient than viral systems, they have received significant attention because they are generally believed to be safer and easier to prepare than viral systems.
A number of non-viral transfection systems involve the use of cationic polymers that are complexed to bioactive agents. Examples of cationic polymers that have been used as gene carriers include poly(L-lysine) (PLL), polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA). Unfortunately, transfection efficiency is typically poor with PLL, and high molecular weight PLL has shown significant toxicity to cells. Unfortunately, PEI-dendrimers have been reported to be toxic to cells, thus limiting the potential for using PEI as a gene delivery tool in applications to human patients.
Dendrimers, as the term is used herein, are a class of polymers often called starburst polymers because of their shape. These dendrimers have a molecular architecture with an interior core, interior layers (or “generations”) of repeating units regularly attached to this interior core, and an exterior surface of terminal groups attached to the outermost generation. These starburst polymers are radially symmetrical and have a branched or tree-like structure. The number of generations can be controlled by the conditions of manufacture, leading to different size molecules having different numbers of terminal groups. U.S. Pat. No. 4,587,329 entitled Dense Star Polymers Having Two Dimensional Molecular Diameter, issued May 6, 1986 to the Dow Chemical Company, the disclosure of which is incorporated by reference, describes these starburst dendrimers and methods of their manufacture. These starburst dendrimers can be made to exact, repeatable molecular weights with the same number of functional groups on each dendrimer. These functional groups can react with a material to be carried, such as a pharmaceutical or agricultural product, or the material to be carried can be associated with this dendrimer in a non-reactive manner.
One family of dendrimers is based on an amidoamine repeat structure, forming what are known as poly(amidoamine) dendrimers (“PAMAM”). PAMAM dendrimers are grown from an amine containing core structure such as ethylene diamine, or the like. Normally ethylene diamine is used as the core or initiator of the reaction. The basic synthesis for PAMAM starburst dendrimers begins with ethylene diamine (EDA) being reacted with methyl acrylate under control conditions such that a Michael addition of one molecule of EDA to four molecules of methyl acrylate occurs. This forms the initiator or core adduct. Following the removal of excess methyl acrylate, the core adduct is reacted with an excess of EDA to form a 0 generation molecule having four amidoamine groups. The excess EDA is removed and the 0 generation molecule can be reacted with methyl acrylate in another Michael addition reaction to form a first generation molecule containing eight primary amine groups. A continuation of this stepwise procedure forms the other generations in sequence.
These delivery systems are being developed to increase the bioavailability of the bioactive agents that are administered. The bioavailability of many compositions is limited when the compound is administered orally. This low bioavailability is often due to incomplete absorption and first-pass metabolism of the compounds. Additionally, rapid degradation of antioxidants in the body fluid and elimination of antioxidants from the body further decreases the beneficial effects of antioxidants. Further, some compounds may be limited by their stoichiometric quantities. By combining the compounds with a dendrimer the goal is to overcome these problems. However, as stated above, currently available systems have met with little to no success. It would therefore be useful to develop a delivery system that both overcomes the problems outlined above as well as increasing the bioavailability of the administered compounds.